Brain Organoids: Studying Human Brain Development and Diseases in a Dish.
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ABSTRACT:
SUBMITTER: Xu J
PROVIDER: S-EPMC8448601 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Human pluripotent stem cells (hPSCs)-derived kidney organoids recapitulate complex developmental processes and tissue architectures, but the intrinsic limitations, such as variability and a lack of vasculature, have greatly hampered their application. Here we establish a highly efficient and versatile protocol for generating vascularized three-dimensional (3D) kidney organoids. We employ dynamic modulation of WNT signaling to control the relative proportion of proximal versus distal nephron segments, thereby producing a correlative level of VEGFA to define the resident vascular network. By single cell RNA-sequencing, we identify a subset of nephron progenitor cells as a potential source of the vasculature. Upon implantation into host mice, these kidney organoids undergo further structural and functional maturation, as demonstrated by the size-selective handling of dextran. Based on this differentiation platform, we establish an in vitro model of autosomal recessive polycystic kidney disease (ARPKD) by differentiating induced PSCs (iPSCs) from an ARPKD patient into 3D kidney organoids that develop tubule cysts in response to cAMP upregulation. The cystogenesis phenotype can be effectively prevented by gene correction or drug treatment. Our studies provide a versatile platform for studying human kidney development and diseases, and opens new avenues for modeling disease pathogenesis and performing patient-specific drug screening.
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Project description:The complexity of the human brain has made it difficult to study many brain disorders in model organisms, highlighting the need for an in vitro model of human brain development. Here we have developed a human pluripotent stem cell-derived three-dimensional organoid culture system, termed cerebral organoids, that develop various discrete, although interdependent, brain regions. These include a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids are shown to recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells. Finally, we use RNA interference and patient-specific induced pluripotent stem cells to model microcephaly, a disorder that has been difficult to recapitulate in mice. We demonstrate premature neuronal differentiation in patient organoids, a defect that could help to explain the disease phenotype. Together, these data show that three-dimensional organoids can recapitulate development and disease even in this most complex human tissue.
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Project description:Human brain organoids are emerging models to study human brain development and pathology as they recapitulate the development and characteristics of major neural cell types, and enable manipulation through an in vitro system. Over the past decade, with the advent of spatial technologies, mass spectrometry imaging (MSI) has become a prominent tool for metabolic microscopy, providing label-free, non-targeted molecular and spatial distribution information of the metabolites within tissue, including lipids. This technology has never been used for studies of brain organoids and here, we set out to develop a standardized protocol for preparation and mass spectrometry imaging of human brain organoids. We present an optimized and validated sample preparation protocol, including sample fixation, optimal embedding solution, homogenous deposition of matrices, data acquisition and processing to maximize the molecular information derived from mass spectrometry imaging. We focus on lipids in organoids, as they play critical roles during cellular and brain development. Using high spatial and mass resolution in positive- and negative-ion modes, we detected 260 lipids in the organoids. Seven of them were uniquely localized within the neurogenic niches or rosettes as confirmed by histology, suggesting their importance for neuroprogenitor proliferation. We observed a particularly striking distribution of ceramide-phosphoethanolamine CerPE 36:1; O2 which was restricted within rosettes and of phosphatidyl-ethanolamine PE 38:3, which was distributed throughout the organoid tissue but not in rosettes. This suggests that ceramide in this particular lipid species might be important for neuroprogenitor biology, while its removal may be important for terminal differentiation of their progeny. Overall, our study establishes the first optimized experimental pipeline and data processing strategy for mass spectrometry imaging of human brain organoids, allowing direct comparison of lipid signal intensities and distributions in these tissues. Further, our data shed new light on the complex processes that govern brain development by identifying specific lipid signatures that may play a role in cell fate trajectories. Mass spectrometry imaging thus has great potential in advancing our understanding of early brain development as well as disease modeling and drug discovery.
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Project description:The discoveries of human pluripotent stem cells (PSCs) including embryonic stem cells and induced pluripotent stem cells (iPSCs) has led to dramatic advances in our understanding of basic human developmental and cell biology and has also been applied to research aimed at drug discovery and development of disease treatments. Research using human PSCs has been largely dominated by studies using two-dimensional cultures. In the past decade, however, ex vivo tissue "organoids," which have a complex and functional three-dimensional structure similar to human organs, have been created from PSCs and are now being used in various fields. Organoids created from PSCs are composed of multiple cell types and are valuable models with which it is better to reproduce the complex structures of living organs and study organogenesis through niche reproduction and pathological modeling through cell-cell interactions. Organoids derived from iPSCs, which inherit the genetic background of the donor, are helpful for disease modeling, elucidation of pathophysiology, and drug screening. Moreover, it is anticipated that iPSC-derived organoids will contribute significantly to regenerative medicine by providing treatment alternatives to organ transplantation with which the risk of immune rejection is low. This review summarizes how PSC-derived organoids are used in developmental biology, disease modeling, drug discovery, and regenerative medicine. Highlighted is the liver, an organ that play crucial roles in metabolic regulation and is composed of diverse cell types.
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